This invention is concerned with compounds of the formula 
where
X is xe2x80x94C(xe2x95x90O)NR3xe2x80x2xe2x80x94, xe2x80x94NR3xe2x80x2C(xe2x95x90O), xe2x80x94C(xe2x95x90NCN)NR3xe2x80x2xe2x80x94, xe2x80x94NR3xe2x80x2C(xe2x95x90NCN)xe2x80x94, xe2x80x94CH2NR3xe2x80x2xe2x80x94, xe2x80x94CH(alkyl)NR3xe2x80x2xe2x80x94xe2x80x94CH(COOalkyl)NR3xe2x80x2xe2x80x94, xe2x80x94CH(CH2OH)NR3xe2x80x2xe2x80x94, xe2x80x94C(CH2Oalkyl)xe2x80x94;
R1 is halo, alkyl cycloalkyl, alkyl(cycloalkyl), aryl, (aryl)alkyl, (aryl)alkenyl, (aryl)alkynyl, O-alkyl, O-alkenyl, O-aryl, O-alky(aryl), O-alkyl(heterocyclo), COO-alkyl, CO-alkyl, CO-amino, CO-substituted amino, alkyl-CO-amino, alkyl-CO-substituted amino, NHCO-alkyl, NHCO-aryl, NHCO-alkyl(aryl), NHCO-alkyl(heterocyclo), N(alkyl)CO-alkyl, N(alkyl)CO-aryl, N(alkyl)CO-heterocyclo, N(alkyl)CO-alkyl(aryl), N(alkyl)CO-alkyl(heterocyclo);
R2 is hydrogen, alkyl, halo, aryl, (aryl)alkyl, O-alkyl, amino, substituted amino;
R3 and R3xe2x80x2 can be the same or different and are independently selected from hydrogen, alkyl, alkyl(aryl);
R4 which can be bonded to a ring carbon or nitrogen, is selected from hydrogen, alkyl, alkenyl, alky(aryl), alkyl(heterocyclo), cycloalkyl, alkyl(cycloalkyl), alkyl-(amino), alkyl-(substituted amino), alkyl-NHCO(alkyl), alkyl-NHCO(aryl), alkyl-NHCO(heterocyclo), alkyl-NHCO(alkylaryl), alkyl-NHCO(alkylheterocyclo); and n is an integer of 0 to 2.
These compounds are useful in the treatment of arrhythmia. The invention is also concerned with pharmaceutical compositions comprising one or more of the novel compounds as an active antiarrhythmic agent either alone or in combination with other cardiovascular agents such as a B-blocker or other antiarrhythmic agent; and a method of treating arrhythmia by administration of one of the novel compounds or compositions thereof to a patient in need of such treatment.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The term xe2x80x9calkylxe2x80x9d refers to both straight and branched chain groups having 1 to 8 carbon atoms, preferably 1 to 5 carbons, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the various branched chain isomers thereof, such as isopropyl, t-butyl, isobutyl, isohexyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl and the like; as well as such groups substituted by, one or more substituents such as halo, alkoxy, amino, substituted amino, aryl, cycloalkyl, hydroxy, heterocyclo, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, alkylthio and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to alkyl-Oxe2x80x94.
The term xe2x80x9calkylthioxe2x80x9d refers alkyl-Sxe2x80x94.
The term xe2x80x9calkenylxe2x80x9d refers to any of the above alkyl groups further containing at least one carbon to carbon double bond.
The term xe2x80x9calkynylxe2x80x9d refers to any of the above alkyl groups further containing at least one carbon to carbon triple bond.
The term xe2x80x9calkanoylxe2x80x9d refers to alkyl-C(O)xe2x80x94.
The term xe2x80x9ccycloalkylxe2x80x9d refers to saturated cyclic hydrocarbon groups containing 3 to 8 ring carbons optionally substitued with one or more substituents such as alkyl or hydroxy.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to chlorine, bromine, iodine and fluorine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, 1-naphthyl, 2-naphthyl, phenanthrene or dihydrophenanthrene; or such groups substituted with one or more substituents such as alkyl, alkylthio, alkoxy, halo, nitro, cyano, hydroxy, amino, substituted amino, phenyl, xe2x80x94C(O)-phenyl, substituted phenyl, xe2x80x94C(O)-substituted amino, heterocycle, carboxylic acid or carboxylic ester.
The term xe2x80x9carylxe2x80x9d also includes those groups listed above fused to a five- or six-membered ring which optionally contains an oxygen, sulfur or nitrogen atom. The five- or six-membered ring may further optionally be substituted with for example, alkyl or -phenyl-CF3.
The term xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheteroxe2x80x9d refers to fully saturated or unsaturated rings of five or six atoms containing one or two oxygen and/or sulfur atoms and/or one to four nitrogen atoms provided that the total number of hetero atoms in the ring is four or less. Exemplary monocyclic heterocyclo groups include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl and imidazolyl.
The term heterocyclo or hetero also includes bicyclic rings wherein the five- or six-membered ring containing oxygen and/or sulfur and/or nitrogen atoms as defined above is fused to a benzene ring and the bicyclic ring is attached by way of an available atom.
Exemplary bicyclic hetero groups include 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-isoquinolinyl, 4-, 5-, 6- or 7-benzothiazolyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or 7-benzoxadiazolyl and 4-, 5-, 6- or 7-benzofuranzanyl.
The term heterocyclo or hetero also includes such monocyclic and bicyclic rings wherein an available atom is substituted by one or more substituents such as alkyl, aryl, alkylthio, alkoxy, halo, nitro, keto, cyano, hydroxy, azo, oxo, thiazo, amino, substituted amino, carboxylic acid, carboxylic ester, or alkoxy further substituted with a carboxylic acid or a five- to eight-membered ring optionally containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, optionally substituted by groups such as alkyl or halogen.
The term xe2x80x9csubstituted aminoxe2x80x9d refers to a group of the formula xe2x80x94NZ1Z2 wherein Z1 is hydrogen, alkyl, cycloalkyl, aryl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl and Z2 is hydrogen, alkyl, cycloalkyl or aryl further substituted with a carboxylic acid or carboxylic ester, provided that when Z1 is hydrogen, then Z2 is other than hydrogen; or Z1 and Z2 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, aryl or hydroxy.
Throughout the specification, groups and substituents thereof are chosen to provide stable moieties and compounds.
The compounds of formula I form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
The compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts may be obtained, for example, by exchanging the carboxylic acid protons, if they contain a carboxylic acid, in compound I with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. Other salts can be formed as known to those having ordinary skill in the art.
The compounds of formula I may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts may be formed by reacting compound I in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
In addition, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed.
A compound of the formula I may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound of formula I) is a prodrug within the scope and spirit of the invention.
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);
b) Methods in Enzymology, Vol. 42, 309-396, edited by K. Widder et al. (Academic Press, 1985);
c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
Bundgaard, Chapter 5, xe2x80x9cDesign and Application of Prodrugs,xe2x80x9d by H.
Bundgaard, 113-191 (1991);
d) Advanced Drug Delivery Reviews, H. Bundgaard, 8, 1-38 (1992);
e) Journal of Pharmaceutical Sciences, H. Bundgaard et al., 77, 285 (1988); and
f) Chem Pharm Bull, N. Kakeya et al., 32, 692 (1984).
It should further be understood that solvates (e.g., hydrates) of the compounds of formula I are also within the scope of the present invention. Methods of solvation are generally known in the art.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in diastereomeric forms or in mixtures thereof. The below described processes can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
The compounds of formula I are useful in the treatment of arrhythmia. More specifically, the compounds of the present invention have the pharmacological properties required for the antiarrhythmic agents of Class III.
Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration. Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na+ or Ca2+ currents; hereinafter INa and ICa respectively) or by reducing outward repolarizing potassium (K+) currents. The delayed rectifier (IK)K+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (Ito) and inward rectifier (IK1)K+ current are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that IK consists of two pharmacologically and kinetically distinct K+ current subtypes, IKr (rapidly activating and deactivating) and IKs (slowly activating and deactivating).
Most Class III agents that are known to be in development predominantly block IKr. These agents have a potential liability in that they have an enhanced risk of proarrhythmia at slow heart rates. The compounds of the present invention prolong the mycocardial action potential in vitro without a significant depression of the Vmax and with the prolongation of Qtc-interval in anesthetized dogs. In addition the compounds of the present invention selectively block IKs. The preferred compounds of the present invention are those which have selectivity of IKs:IKr greater than or equal to 5.
The compounds of the present invention are effective in treating and preventing all types of arrhythmias including ventricular and atrial (supraventricular) arrhythmias. The compounds of the present invention are especially useful to control reentrant arrhythmias and prevent sudden death due to the ventricular fibrillation.
In the novel method of this invention of treating arrhythmia, a novel compound or pharmaceutically acceptable salt thereof, is administered in an amount ranging from about 0.0001 to about 20 mg per kg of body weight per day, preferably from about 0.001 to about 10 mg per kg of body weight per day in a single dose or in 2 to 4 divided doses.
The novel compounds of this invention can be administered as the sole active ingredient or in combination with other antiarrhythmic agents or other cardiovascular agents.
The compounds, or pharmaceutically acceptable salts thereof, of the present invention, in the described dosages, are administered orally, intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously. They are preferably administered orally, for example in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, or the like prepared by art recognized procedures. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
The preferred compounds of the present invention are those compounds of formula I where:
X is xe2x80x94C(xe2x95x90O)NR3xe2x80x2xe2x80x94, xe2x80x94NR3xe2x80x2C(xe2x95x90O)xe2x80x94, xe2x80x94CH(CH2OH)NR3xe2x80x2xe2x80x94,
R1 is alkoxy;
R2 is hydrogen;
R3 and R3xe2x80x2 are the same or different and are independently selected from hydrogen or alkyl;
R4 is hydrogen, alkyl(heterocyclo), alkyl(substituted amino); and
n is an integer of 0 to 2.
The compounds of the instant invention can be obtained by methods exemplified by the following descriptions.
Compounds of formula IA, which are compounds of formula I wherein R3 is hydrogen, n=0-2 and R4 is alkyl-substituted amino, can be prepared according to Scheme 1. 
The compound of formula 1 is alkylated with ethyl bromoacetate in the presence of a base and the resulting compound 2 is reduced with a reducing agent such as LiBH4. The alcohol in product 3 is converted to a leaving group (e.g., mesylate, halide etc.) and displaced with an amine to provide the target compound IA.
Compounds of formula 1 are known in the literature (e.g, J. Chem. Soc., 1969, p 183) and other reagents employed in Scheme I are either commercially available or they can be prepared by literature methods.
Compounds of formula IA, can also be prepared according to Scheme 2. 
The compound of formula 1 is alkylated with allyl bromide in the presence of a base and the resulting compound 5 is treated with ozone followed by NaB(OAc)3H to provide the aldehyde 6. Reductive amination of 6 with an amine of formula Z1Z2NH provides the requisite compounds of formula IA.
The reagents employed in Scheme 2 are either commercially available or they can be prepared by literature methods.
Compounds of formula IC and ID are compounds of formula I wherein X is xe2x80x94C(xe2x95x90O)N or xe2x80x94NC(xe2x95x90O)xe2x80x94 and n=0-1 and can be prepared according to Scheme 3. 
The ketone of formula 7 is alkylated with a suitable alkylating agent once or twice (depending on the substituents R3 and R4). The resulting compound 8 is converted to a mixture of oximes 9 by treatment with hydroxyl amine hydrochloride and sodium acetate. The oxime 9 undergoes Beckmann rearrangement in methanesulfonic acid to provide the desired products IC and ID. Alternatively, compounds IC and ID can be directly prepared from ketone 8 by treatment with sodium azide in the presence of sulfuric acid. The ratio of IC to ID depends on the substituents R3 and R4 and the reaction conditions employed.
Compounds of formula 7 are commercially available or they can be prepared by methods known in the literature methods.
Compounds of formula IE which are compounds of formula I wherein X is xe2x80x94C(CH2OH), R3 is hydrogen, n=1 and R4 is alkyl-substituted amino, can be prepared from 1 as described in Scheme 4. 
The amine in 10 is alkylated with an appropriate alkylating agent (e.g., ter-Butylbromoacetate) in the presence of a base (e.g., potassium carbonate). The ter-butyl group in 11 can be removed by acid treatment and the resulting acid 12 is coupled with an amine of formula Z1Z2NH under standard conditions. The amide in 13 is reduced to provide compounds of formula IE.
Compounds of formula 10 are described in the literature (W. K. Anderson, H. L. McPherson, J. S. New and A. C. Rick, Journal of Medicinal Chemistry, Vol. 27, p. 1321, 1984) and other reagents used in Scheme 4 are either commercially available or they can be prepared according to methods described in the literature.
Various reactive groups (e.g., amine, hydroxyl) that can potentially interfere with the reaction sequence described in Schemes 1-4, are protected with appropriate protecting groups such as those described in the literature. The protecting groups are removed after the requisite transformations.